6 Research highlights: Chronic fatigue syndrome and XMRV - reasons why the BMJ
fast tracked the Dutch XMRV study and critical comments about the media
publicity that accompanied publication of the Science paper in October 2009
(p516)

7 Fast Track Research: Prevalence of XMRV in patients with chronic fatigue
syndrome in the Netherlands: retrospective analysis of samples from an
established cohort (summary of key points on p520)

fgodlee@bmj.com
The lively response to last month’s editorial on chronic fatigue syndrome (BMJ 2010;340:c738, doi:10.1136/bmj.c738) brings home the inadequacy of our current understanding of this condition, or group of conditions. The responses from patients, carers, and clinicians remind us that we remain largely in the dark about its causes and prognosis, there are no accepted diagnostic tests, and treatment options are limited (www.bmj.com/cgi/eletters/340/feb11_1/c738). Sufferers must also deal with social and (if they are doctors) professional stigmatisation, as dermatologist Stephanie Munn experienced (doi:10.1136/bmj.c1179).

Little wonder if many who live or work with chronic fatigue syndrome leapt at the news last October that scientists in Nevada had found a "highly significant association" between the condition and a newly discovered retrovirus, xenotropic murine leukaemia virus-related virus (XMRV). The case-control study published in Science was trumpeted, especially by the authors, as having found the cause of chronic fatigue syndrome, with promises of a diagnostic test and treatments to follow.

As an epidemiologist, Cathie Sudlow’s initial response was sceptical, quickly confirmed when she saw that the paper lacked basic methodological information (doi:10.1136/bmj.c1260). "Where were the details of the characteristics and selection procedures for the cases and controls, or of blinding of researchers to the case-control status of the samples? Where was the discussion of the potential role of bias and confounding?"

She and others sent electronic letters to the journal. Four months on, these have yet to appear. Meanwhile, and sadly for those whose hopes had been raised, the study has been refuted by three further case-control studies, one of them in the BMJ (doi:10.1136/bmj.c1018). Myra McClure and Simon Wessely point out that claims of association between retroviruses and diseases often fail to withstand the test of time (doi:10.1136/bmj.c1099).

The paper by Van Kuppeveld and colleagues is an unusual paper for the BMJ to publish. As our research highlights page explains, we would usually reject a small case-control study examining the prevalence of a virus in 20 year old blood samples. Instead we fast tracked it. We did this because it’s about an important and debilitating syndrome that’s often seen by generalists and because we felt it added to an important and highly controversial debate. We and our reviewers also thought it was well done.

So yes, let’s have more research into chronic fatigue syndrome, but let’s make sure it’s good enough research.

We’re all under pressure to innovate, so we need to ensure as far as possible that innovation brings improvement. This may not be the case with the new edition of America’s (and hence the world’s) Diagnostic Criteria for Psychiatric Disorders. Three years in the drafting, DSM-V is now out for consultation with a view to publication in 2013.

Our editorialist cries caution (doi:10.1136/bmj.c1168). DSM-IV was unwittingly responsible, says Allen Frances, for three "epidemics" of overdiagnosis. Rates of attention deficit hyperactivity disorder, autism, and childhood bipolar disorders shot up when it was published, fuelled not only by DSM-IVs more inclusive diagnostic criteria but by zealous marketing of drugs to doctors and the public.

Now DSM-V threatens worse. It widens the criteria for several existing diagnoses and creates five new ones: binge eating, mixed anxiety depression, minor neurocognitive problems, risk of psychosis, and temper dysregulation. This could "expand the territory of mental disorder and thin the ranks of the normal," exposing vast numbers of new "patients" to avoidable harm.

Interesting stuff; Suzanne Vernon wasn't the only one worried about that cohort and the methodology. On the hand Gerwyn will love the stuff on those old samples.

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Hardly interesting stuff Cort (other than the admittance of using 20-year old blood). The BMJ is the standard party medical journal in the UK, an unreserved apologist for the failings of the medical profession over the last 25 years. Not what I would call a neutral observer by any means.

They have absolutely no incentive to solve CFS. Their vested interest lies only in maintaining the status quo.

BMJ: So yes, let’s have more research into chronic fatigue syndrome, but let’s make sure it’s good enough research.

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I read that as: "Let's have more research, but lets make sure its psychological based research. How dare you look at infectious causes for this disease."

Well it was interesting to me. I don't know BMG well. I thought it was interesting, that yes, other researchers have had similar concerns as Dr. Vernon - and yes, for whatever reason, the WPI has ignored requests for more information. We all want WPI to succeed but on this issue, for whatever reason, they've refused to provide more light.

BMJ basically called one on themselves -tried to squirm out of an embarrassing situation - I've never seen that before! - so that was interesting to me as well. I hope we can get the other articles on the Journal. Here's my response on the XMRV buzz page I have:

BMJ on XMRV - citing the 'lively' response to their publication of a recent editorial on CFS, the British Medical Journal did what any media outlet would do when confronted with a hot story; they put XMRV on the front page of their journal and packed the Journal with XMRV articles; this was XMRV month at the BMJ. Lively was indeed the word for the 30 odd responses the Journal received, many of them lengthy and most of them taking the Journal to task for another behavioral, CBT promoting editorial on CFS.

The UK is as we know ground zero for the behavioral interpretation of ME/CFS The polite but condescending PR speak was, of course, present....the concern over the patients....blah, blah, blah. They noted, which we have heard, their concern over the patient cohort and the controls and the fact that their (and everyone else's) attempts at getting more information from the WPI failed. They went over the negative results and then admitted that they had rushed the last paper through to publication; a paper that in some respects, failed their standards. (An rather odd revelation from a paper called "Let's Proceed with Caution") They closed the piece in a rather snarky way appealing for research that this time, will be good enough. (No one beats the British at the velvet gloved knife in the back ).

They went over the negative results and then admitted that they had rushed the last paper through to publication; a paper that in some respects, failed their standards. (An rather odd revelation from a paper called "Let's Proceed with Caution") They closed the piece in a rather snarky way appealing for research that this time, will be good enough. (No one beats the British at the velvet gloved knife in the back ).

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Good editorial here.

I love their call for more research and their faux concern for this community. Where is this research supposed to come from? There is no funding in this country for biomedical research into ME/CFS. Why don't they do a story on that.

Well it was interesting to me. I don't know BMG well. I thought it was interesting, that yes, other researchers have had similar concerns as Dr. Vernon - and yes, for whatever reason, the WPI has ignored requests for more information. We all want WPI to succeed but on this issue, for whatever reason, they've refused to provide more light.

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This concerns me alot too. Does anyone have any info or can shed any light on this situation? We (WPI and other ME researchers and advocates) need to be punctilious in our methods and presentation so that others can not accuse us of logical flaws or trying to hide something as we (rightly) accuse those of the Wessely school and others.

The UK is as we know ground zero for the behavioral interpretation of ME/CFS The polite but condescending PR speak was, of course, present....the concern over the patients....blah, blah, blah. They noted, which we have heard, their concern over the patient cohort and the controls and the fact that their (and everyone else's) attempts at getting more information from the WPI failed. They went over the negative results and then admitted that they had rushed the last paper through to publication; a paper that in some respects, failed their standards. (An rather odd revelation from a paper called "Let's Proceed with Caution") They closed the piece in a rather snarky way appealing for research that this time, will be good enough. (No one beats the British at the velvet gloved knife in the back ).

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Yes, more maudlin b.s. fake concern for patients and how horrible it is that charlatans like WPI try to mislead us with false hope. How dare they imply that WPI/CC/NCI study was not 'good enough' and that the dutch study which used the Oxford criteria was! The Oxford criteria is blatently invalid and thus any study that uses it is invalid. End of Story.

In the linked case-control study (doi:10.1136/bmj.c1018), van Kuppeveld and colleagues describe their failure to find evidence of a new human retrovirus in Dutch patients with chronic fatigue syndrome.1 The study is the latest contribution to a controversy that has surrounded two conflicting publications on the retroviral aetiology of this syndrome.2 3

The saga started, not with chronic fatigue syndrome or a virus, but with an enzyme (RNaseL) that plays a pivotal role in antiviral defences when activated by the interferon released in response to infection. Variants of the gene encoding this enzyme have been linked to an increased susceptibility to prostate cancer, and this led to the identification of a new virus in prostate tissue that was related to, but different from, known xenotropic murine leukaemia viruses4; hence the designation xenotropic murine leukaemia virus-related virus (XMRV). Sequence analyses showed that it is not an endogenous human virus, and the fact that eight clones derived from eight different patients are slightly different from one another confirms it as a new virus that has found its way into a human population.

Abnormalities in the RNaseL gene of patients with chronic fatigue syndrome had been reported in some studies,5 but not in others.6 Nevertheless, this prompted the search for evidence of XMRV in patients with chronic fatigue syndrome. The resulting study claimed that 67% of patients with chronic fatigue syndrome were XMRV carriers, compared with 3.7% of healthy controls.2

The news was received philosophically by most retrovirologists, who are used to claims of associations between retroviruses and diseases that fail to withstand the test of time. Most researchers into chronic fatigue syndrome were also sceptical, mindful of the problems of defining the syndrome, its imprecise boundaries, and almost certain heterogeneity. It was not that they doubted a viral cause in some patients because this had already been shown,7 8 but the possibility that any single agent or risk factor could account for more than two thirds of cases seemed implausible on the basis of what has already been established.9

But if the research community was underwhelmed, people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals who believe that, irrespective of causation, rehabilitative treatments can reduce symptoms and disability. It is depressing that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence.

First and foremost, however, as with any discovery, the data must be unequivocal, and the finding has to be confirmed by others. In January 2010, our own group found no evidence of XMRV in a well characterised cohort of 186 patients with chronic fatigue syndrome in the United Kingdom.3 Van Kuppeveld and colleagues’ study adds to this negative evidence. Although the study is small, the patients are well defined and matched in age, sex, and geographical location. The polymerase chain reaction used to amplify XMRV gene sequences has been well controlled and its sensitivity is sufficient to detect low virus copy numbers. XMRV was not detected in this Dutch cohort, a result that comes in the wake of a third study published this month,10 which also failed to identify XMRV in 170 patients with chronic fatigue syndrome.

There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant provided amplification is controlled by inclusion of a "housekeeping gene"—to show that a known human gene can be amplified under the conditions used—and the sensitivity of the assay is known, as was the case in all three European studies.

Meanwhile, a different strategy is also being considered to reconcile these different findings: that new blood samples should be taken from patients with diagnosed chronic fatigue syndrome and sent to laboratories capable of carrying out the analysis. This is unlikely to be soon.

Three studies have now generated data that are in stark contrast to those of the original study. However, at least two explanations for this are still possible. The first, and more unlikely, explanation is that XMRV infection is geographically confined to the United States. The second is that the virus is infecting an atypical cohort. This may well be so. Although the patients were not well described in the original study, van Kuppeveld and colleagues provide the additional information reported at a conference last year that the patients in question came from an outbreak of chronic fatigue syndrome at Incline village on the northern border of Lake Tahoe in the mid-1980s. Whether or not this was a genuine cluster was never established,11 but an association with viruses, such as Epstein-Barr virus and human herpesvirus 6, has already been suggested.12 It is possible that XMRV is implicated in the Lake Tahoe episode but does not play a substantial role in most cases of chronic fatigue syndrome elsewhere.

The results from other US laboratories investigating XMRV and chronic fatigue syndrome are eagerly awaited. If the link fails to hold up, it will be another bitter disappointment to affected patients. Nonetheless, the current debate will still bring critical attention to the causes of chronic fatigue syndrome, and XMRV may turn out to be important in the pathogenesis of other diseases.

Were the majority of "CFS" researchers dismissive of the finding as he claims or just his crew of fake "CFS" scientists/ insurance shills? Rhetorical Question.

As usual Wessely et al. say it's not possible for there to be singular cause for the majority of "CFS" cases since "CFS" is so heterogenous and it doesn't have clear boundaries. And as usual they are talking about their own bogus Oxford definition they made up to cause confusion and doubt. Their usual circular logic.

Does anyone have a take on the below:

There has been much talk of different protocols being used in the four studies. These technical differences are irrelevant provided amplification is controlled by inclusion of a "housekeeping gene"—to show that a known human gene can be amplified under the conditions used—and the sensitivity of the assay is known, as was the case in all three European studies.

The issue is this- take two distinct illnesses, anorexia nervosa and cancer, both of which are characterized by weight loss. Then create a waffling name such as Chronic Weightloss Syndrome, or CWS, and allow individuals such as Prof. Wessely and his colleagues to pollute the CWS research literature with studies characterized by all manner of vague inclusion criteria and questionable methodologies which end up showing whatever it is the authors designed them to show. Then trumpet these false studies in uncritical and biased medical journals such as the BMJ instead of rigourous and well done studies on well defined patient groups.

I don't know a great deal about the Defreitas study, is it possible the virus Defreitas found was XMRV?

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Hi Knackered,

In November, WPI on Facebook posted a notice under the "Notes" Tab on its Facebook site in connection with the work of Defreitas. I can no longer locate a "Notes" section on the WPI Facebook site but I archived a copy on my own site, in this ME agenda posting:

the publication and patent submitted by De Freitas et all clear describe the molecular characteristics of a retrovirus that is not a gamma (type C) retrovirus. The patent submitted for the retroviruses states

Chronic Fatigue Immunodeficiency Syndrome associated virus, hereafter referred to by the name CAV may be morphologically characterized as a retrovirus, particularly a non-C retrovirus which is capable of infecting humans. Electron microscopy of viral particles formed in infected human cell cultures suggests that CAV is a non-C type retrovirus because of its diameter, morphology, formation and location of intracellular virions. The Electon micrographs of XMRV shown in Lombardi et al clearly depict a budding type C retrovirus of 90-100microns The DeFritas patent goes on to say More specifically, CAV-infected cells could be characterized by electron-dense circular virions, some with electron-luscent cores and others with electron-dense cores, associated with the rough endoplasmic reticulum and inside large abnormally distended mitochondria in the cells. All particles are the same shape and size, 46-50 nm. No extracellular virus is observed. No forms budding from the cytoplasmic membranes are observed.

Thus, CAV-infected cells could also be charcterized by the presence of intracytoplasmic particlesGamma (type C) retroviruses are 90 1100uM as shown in Lombardi et al and all are shown to consist of electron dense cores and specifically to bud extra-cellularly not intracellularly.

The issue is this- take two distinct illnesses, anorexia nervosa and cancer, both of which are characterized by weight loss. Then create a waffling name such as Chronic Weightloss Syndrome, or CWS, and allow individuals such as Prof. Wessely and his colleagues to pollute the CWS research literature with studies characterized by all manner of vague inclusion criteria and questionable methodologies which end up showing whatever it is the authors designed them to show. Then trumpet these false studies in uncritical and biased medical journals such as the BMJ instead of rigourous and well done studies on well defined patient groups.

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My comment to the podcast:

BMJ: Helping Doctors Make Worse Decisions
John hits the core issue right on the head. The "Wessely School" came up with and use the patently flawed "Oxford 1991" definition of "CFS", which is merely idiopathic chronic fatigue, i.e. nothing more than chronic tiredness not caused by a known disease.1 This is a transparent attempt to create confusion and doubt by lumping all unknown causes of fatigue into "CFS" rather than defining ME/CFIDS as the unique neuro-endocrine immune disease it is. BMJ continues to publish studies based on the spurious Oxford definition despite receiving critiques every time they publish these invalid studies. This Oxford definition is used by the Wessely School, including the Dutch researchers in this issue of BMJ, to produce meaningless results so they can say 'let's just treat them with CBT and GET (graded exercise)."

A hallmark of ME/CFIDS is Post-Exertional Morbidity- the worsening of the disease upon minimal exertion. The Wessely School CBT/GET treatment is: telling patients they do not have an organic disease, that exercise has been proven to only help, not harm them and then making patients exercise. This results in a tremendous amount of iatrogenic physical morbidity.2 Unlike the Oxford definition, the Canadian Government ME/CFS Definition created by consensus of many of the world's top ME/CFIDS clinicians and researchers, deliniates and explains the (considerable known) pathophysiolgy of this discrete disease.3

Wessely says, in the accompanying podcast, that even were XMRV found to be the cause of ME, the exclusive treatment would remain CBT/GET. Well, is the treatment for AIDS still to tell patients they don't have illness other than symptoms caused by the stress of being gay and they just need to exercise? History has shown that finding a retroviral cause and treating with anti-retrovirals significantly reduces patients' illness burden even more than Wessely's therapy of telling a patient he is not really sick.

For the story of the Wessely School's war on science and ME patients, please see Prof. Malcolm Hooper's recently published "Magical Medicine" free, infra.4

I wonder how longed they worked to hone the verbiage in this paragraph:

"But if the research community was underwhelmed, people with the syndrome were not. If true, these findings would have transformed the understanding of the illness and opened up new avenues of treatment. Some saw this as a definitive response not only to those few professionals who, they claim, continue to doubt the reality of the syndrome, but also to the larger number of professionals who believe that, irrespective of causation, rehabilitative treatments can reduce symptoms and disability. It is depressing that the first, untenable, view is too often confused with the second, a perspective that offers hope to patients and is backed by evidence."

...research community underwhelmed????? Not true.

"It is DEPRESSING..." Really? They are depressed that the CFS/ME community doesn't see a difference between the professionals who doubt the reality of the syndrome with those who offer bogus treatments, "backed by evidence".

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Exactly. Wessley is smart. He sure knows how to pull a scam with carefully crafted and continuous PR. His job title should be UNUM propoganda minister because that literally is his full time job. As we all know, it certainly isn't science.

In the same issue on-line is our boy Wessely and his friends expressing how wonderful it is to be helping the poor "CFS" patients and how XMRV is total BS. He even says that...

EVEN IF XMRV WERE FOUND TO BE THE CAUSE, MEDICAL THERAPIES WOULD BE INAPPROPRIATE!!

He then says "We're not going to go doing more and more tests to find out what was the virus because, frankly, even if we found it there's nothing we're going to do about it. We're in the business of rehabilitation."
(at 10 minutes 20 seconds)

And then the interviewer repeats this uncritically in summary at the end!

The issue is this- take two distinct illnesses, anorexia nervosa and cancer, both of which are characterized by weight loss. Then create a waffling name such as ‘Chronic Weightloss Syndrome’, or ‘CWS’, and allow individuals such as Prof. Wessely and his colleagues to pollute the ‘CWS’ research literature with studies characterized by all manner of vague inclusion criteria and questionable methodologies which end up showing whatever it is the authors designed them to show. Then trumpet these false studies in uncritical and biased medical journals such as the BMJ instead of rigourous and well done studies on well defined patient groups.
-John

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My comment to the podcast:

Post by justinreilly:
BMJ: Helping Doctors Make Worse Decisions
John hits the core issue right on the head. The "Wessely School" came up with and use the patently flawed "Oxford 1991" definition of "CFS", which is merely idiopathic chronic fatigue, i.e. nothing more than chronic tiredness not caused by a known disease.1 This is a transparent attempt to create confusion and doubt by lumping all unknown causes of fatigue into "CFS" rather than defining ME/CFIDS as the unique neuro-endocrine immune disease it is. BMJ continues to publish studies based on the spurious Oxford definition despite receiving critiques every time they publish these invalid studies. This Oxford definition is used by the Wessely School, including the Dutch researchers in this issue of BMJ, to produce meaningless results so they can say 'let's just treat them with CBT and GET (graded exercise)."

A hallmark of ME/CFIDS is Post-Exertional Morbidity- the worsening of the disease upon minimal exertion. The Wessely School CBT/GET treatment is: telling patients they do not have an organic disease, that exercise has been proven to only help, not harm them and then making patients exercise. This results in a tremendous amount of iatrogenic physical morbidity.2 Unlike the Oxford definition, the Canadian Government ME/CFS Definition created by consensus of many of the world's top ME/CFIDS clinicians and researchers, deliniates and explains the (considerable known) pathophysiolgy of this discrete disease.3

Wessely says, in the accompanying podcast, that even were XMRV found to be the cause of ME, the exclusive treatment would remain CBT/GET. Well, is the treatment for AIDS still to tell patients they don't have illness other than symptoms caused by the stress of being gay and they just need to exercise? History has shown that finding a retroviral cause and treating with anti-retrovirals significantly reduces patients' illness burden even more than Wessely's therapy of telling a patient he is not really sick.

For the story of the Wessely School's war on science and ME patients, please see Prof. Malcolm Hooper's recently published "Magical Medicine" free, infra.4